Age-related macular degeneration (“AMD”) is defined by the gradual destruction of sharp, central vision in older individuals. The macular area of the retina processes central vision, and is adjacent to the optic nerve and near the center of the optic axis. AMD occurs in two forms, dry and wet.
Dry AMD is defined by the gradual loss of retinal pigment epithelial (RPE) and photoreceptor cells in the macula. Drusen, or yellow deposits under the retina, are often found in people over 60 and represent an early indication of developing AMD, but do not in and of themselves cause vision loss. Early AMD is defined by several small drusen or less frequent medium-sized drusen. Intermediate AMD is defined by more medium-sized drusen or a few large drusen. At this stage, visual disturbances may be reported. Advanced dry AMD is defined by loss of photoreceptors and supporting cell types in the macula with accompanying progressive vision loss.
Wet AMD is less common and is characterized by growth of abnormal blood vessels beneath the macular epithelium. These vessels are fragile and leak blood and exudates that separate the macular retina from underlying structures. Wet AMD advances more quickly than dry AMD. Rather than blurry vision characteristic of dry AMD, wet AMD is associated with the perception of straight-line grids as wavy especially at their center. The wet form develops in people who initially present with the dry form and is always considered an advanced form of AMD.
Current treatment for dry AMD consists of a regimen of specific high-dose anti-oxidants (vitamins C, E, beta carotene), and copper and zinc (National Eye Institute's Age-Related Eye Disease Study [AREDS] formulation) that reduce the risk of progression of intermediate AMD to advanced AMD. However, this treatment is not indicated for early AMD due to lack of efficacy. Wet AMD is treated with laser surgery to destroy abnormal vasculature but may not be indicated for most cases. New abnormal vessels may develop after initial treatment.
Photodynamic therapy is also used to destroy abnormal vessels.
Yet another treatment option is direct injection of the anti-VEGF (vascular endothelial growth factor) antibody fragment ranibizumab (LUCENTIS, Genentech) which is now approved for the treatment of wet AMD. This treatment may slow vision loss and in some cases actually improves vision. However, it requires intravitreal injection and subsequent monitoring for increases in ocular pressure. Retinal detachment or infection may occur along with red eye, vitreous floaters and pain. In addition, bevacizumab is currently being used off-label as an intravitreal injection to treat AMD (Costa et al., Investigative Ophthamology and Visual Science, 47: 4569-4578, 2006).
Melatonin has been shown to control eye pigmentation (i.e., melanin) and thereby regulate the amount of light that can reach the photoreceptors. Melatonin levels produced by the pineal gland are known to decrease with age in humans, as do levels of melanin in retinal pigment epithelial cells (RPE) (Sarna, T. et al., Exp. Eye Res., 76: 89-98, 2003). Melatonin is also synthesized by photoreceptor cells with a circadian rhythm similar to that of the pineal gland (Weichmann, A. F., Exp. Eye Res., 42: 507-527, 1986). The diminution may decrease the protection from oxidative damage afforded to the RPE by melanin. RPE dysfunction, which is thought to follow oxidative damage, is a well-known initiator of age-related macular degeneration (AMD).
Melatonin has been shown to protect human retinal pigment epithelial (RPE) cells in vitro when added diurnally to RPE cell cultures for three consecutive days. This treatment regimen markedly reduced H2O2-induced cell death and mitochondrial DNA damage (Liang, F.-Q., et al., Exp. Eye Res., 78: 1069-1075, 2004). Other studies have shown that melanin itself protects the human RPE from light-induced apoptosis (Seagle, B.-L. L., et al., Proc. Natl. Acad. Sci. U.S.A., 102: 8978-8983, 2005) and that melanin free radicals can quench reactive oxygen species (Seagle, B.-L. L., et al. J. Am. Chem. Soc., 127: 11220-11221, 2005). These studies are of interest because melatonin, and presumably its analogs, can raise the level of melanin in the RPE.
A case-controlled study of dry and wet AMD has recently shown that 3 mg melatonin administered daily at bedtime for at least three months may reduce the extent of retinal pathology over time. Visual acuity remained stable, and the change in the picture of the fundus was remarkable in that few of the examined eyes showed either more retinal bleeding or exudates (Yi, C. et al., Ann. N.Y. Acad. Sci., 1057: 384-392, 2005).
Melatonin is available over the counter in the US generally as a 3 mg tablet for relief from insomnia or jetlag, but has never been fully tested for efficacy or safety and therefore is sold as an over the counter dietary supplement.
Ramelteon is a melatonin analog described in U.S. Pat. No. 6,034,239 (hereby incorporated by reference in the entirety), and is currently FDA approved for marketing in the US for treatment of sleep disorders. This non-addictive compound is available in an 8 mg tablet, and numerous GCP compliant clinical trials and drug-drug interaction studies have shown that ramelteon is safe for humans at significant multiples of the therapeutic dose. Ramelteon, a sleep-promoting agent, is chemically designated as (S)—N-[2-(1,6,7,8-tetrahydro-2H-indeno-[5,4-b]furan-8-yl)ethyl]propionamide, and is a selective melatonin receptor agonist with high affinity for melatonin MT1/MT2 receptors. As a sleep aid, ramelteon appears to act more as a “switch” rather than exhibiting prominent dose-dependent pharmacology.
Melatonin, melatonin analogues and anti-VEGF agents have all been proposed as useful pharmacological agents for the treatment of glaucoma. Specifically, it has been suggested that melatonin may be useful for the treatment of glaucoma (Lundmark et al., Exp. Eye Res., 84: 1021-1030, 2007; U.S. Pat. No. 4,654,361 and U.S. Patent Application Publication No. 2007/0207116); U.S. Pat. No. 6,034,239 indicates that ramelteon is useful to treat various disorders accompanies by aging, and also that ramelteon may be useful to treat glaucoma; and off-label use of either bevacizumab or ranibuzumab to treat glaucoma with positive results has been reported (Ichhpujani et al., Can. J. Ophthamol., 42: 812-815, 2007; Cheng et al., Annals Academy of Medicine, 37: 72-74, 2008; Dunavoelgyi et al., Clinical and Experimental Ophthamology, 35:878-880, 2007).